The overall objective of this U01 application from the Dana-Farber/Harvard Cancer Center (DF/HCC) is to provide clinical and scientific experience and patient resources to perform Phase I single agent clinical trials* Phase I agent combination clinical trials, limited Phase II clinical trials, and pilot clinical trials of novel anti- cancer agents. These studies will be performed by the DF/HCC Phase I Oncology Group consisting of investigators at the participating Dana-Farber Cancer Institute (DFCI), Brigham and Women's Hospital (BWH), Massachusetts General Hospital (MGH) and the Beth Israel Deaconess Medical Center (BIDMC) sites. The DF/HCC Phase I Oncology Group has interacted over the past 15 years (1992-2007) in the conduct of more than 70 Phase I, l-ll pharmacokinetic and pharmacodynamic clinical trials of investigational new cytotoxic agents, angiogenesis inhibitors, signal transduction/cell cycle inhibitors, differentiating agents and anti-cancer vaccines. Trials performed over the past 4 years (2003-2006, prior funding period) include 10 agents from the NCI Clinical Trials Evaluation Program (CTEP). The DF/HCC Phase I Oncology Group has accrued 219 patients to the 10 CTEP trials during 2003-2006 with an average accrual of 55 patients annually. These trials have been integrated with pharmacokinetic, biochemical, pathological, immunological, molecular and imaging studies that correlate effects of the agents on their targets. The Specific Aims of the DF/HCC application are 1) To perform Phase I, limited Phase II and pilot clinical trials of novel agents in the NCI CTEP IND portfolio that target relevant cancer cell signaling pathways involved in the regulation of cell survival, proliferation, apoptosis, differentiation and angiogenesis; 2) To assess pharmacokinetics of these agents when administered alone or in combination and establish relationships between dose, schedule, exposure and effect; 3) To perform these trials with novel designs where appropriate, including accelerated titration and other advanced design schemes; 4) To establish safe and biologically active treatment schedules for patients with cancer, including those with hepatic and/or renal dysfunction; 5) To obtain mechanistic proof-of-principle data for new agents directed at novel molecular targets; and 6) To evaluate translational endpoints of expression and/or activity of molecular targets and downstream effectors that are regulated by these agents. The importance of this work to the public health is realized by the need for more and better treatment options for the substantial number of cancer patients who, because of disease unresponsive to existing treatments, become candidates for new investigational agents. The research proposed in this U01 agreement is focused on accelerating access of these cancer patients to new treatment strategies.